The radioactive diagnostic imaging agent is a medicine directly administered to a human body and is a pharmaceutical composition containing a compound labeled with a specific radioisotope as an effective ingredient. The radioactive diagnostic imaging agent enables diagnosis by administering an agent to a subject and detecting a radiation emitted from the compound, followed by imaging based on information obtained from the radiation. The thus-conducted diagnosing method is referred to as nuclear medicine examination, and is effective in diagnosing a variety of diseases including heart disease and cancer. Also, nuclear medicine examination is characteristic in that it has not only high specificity and sensitivity to diseases, but also has an advantage of providing information on the functionality of lesions, compared to other examination techniques.
Compounds which are researched and developed as such radioactive diagnostic imaging agents include 1-amino-3-[18F]fluorocyclobutanecarboxylic acid (hereinafter referred to as [18F]-FACBC). It is known that [18F]-FACBC is taken up into a cell via an amino acid transporter. Thus, [18F]-FACBC is expected to be developed as a tumor diagnostic agent since it is largely taken up into tumor cells which are highly proliferative and active in protein synthesis.
In radioactive diagnostic imaging agents, a problem often arises such that compounds decompose by self-radiation during delivery of the agents so as to cause decrease in radiochemical purity due to so-called radiolysis. Particularly, in PET agents for detection of positron nuclides such as 18F, radiolysis often becomes more problematic since the half-life of the nuclides used therein is shorter than that of nuclides used in SPECT agents for detection of gamma-ray emitting nuclides such as 99Tc, and thus radioactivity upon shipment must be set larger than SPECT agents, thereby making the resulting radiation energy thereof higher.
For general pharmaceuticals, it is recommended in the guideline of ICH that if impurities in an agent exceed 1.0%, the impurities be subjected to structure determination when the maximum daily dosage of an effective component thereof is as small as not more than 1 mg (Non-Patent Document 1). In most cases, the physical amount of impurities resulting from the radiolysis which may be considered to be one aspect of the decomposition of an agent is as small as about 10−12 mol, even if it exceeds 1.0%. Since the production amount of impurities such as radioactive decomposed matters is minute, structure determination of the impurities by NMR analysis is difficult even though only determination of molecular weight and presumption of their fragments can be made by mass spectrometry which is excellent in detection sensitivity. Also, it is very difficult to conduct verification as to whether or not the impurities affect effectiveness such as tumor accumulation of the agent.
Therefore, impurities in the radioactive diagnostic imaging agent should be maintained as low as possible, and it is preferable that radiolysis which may cause the production of impurities should also be inhibited as much as possible.
Various methods for inhibiting radiolysis have been examined focusing on application to [18F]-fluorodeoxyglucose (hereinafter referred to as [18F]-FDG).
International Publication No. WO03/090789 pamphlet discloses a method of reducing the radiolysis of [18F]-FDG by adding a weak acid-based buffer to a [18F]-FDG solution and an injection prepared by the method (Patent Document 1). Also, International Publication No. WO04/043497 pamphlet discloses adding ethanol to a [18F]-FDG solution to obtain a composition of injection which may be reduced in radiolysis of [18F]-FDG to improve stability (Patent Document 2).
Japanese Patent Laid-open (Kokai) No. H10-147542 discloses a technique utilizing an organic compound high in physiological acceptability such as monosaccharides, disaccharides, organic acids and salts or esters thereof as a radiation protecting agent (Patent Document 3). In this publication, the organic compound high in physiological acceptability and particularly effective as the radiation protecting agent is defined to have a reaction rate constant with OH radicals, H radicals or hydrated electrons in the range of 1×108 to 5×1010 mol−1s−1.
International Publication No. WO04/056725 pamphlet discloses a solid-phase synthesis method for 18F-labeled tracers including [18F]-FACBC (Patent Document 4). In this document, it is suggested that radiolysis of 18F-labeled tracers is reduced by adding ascorbic acid to a composition of injection.    Non-Patent Document 1: ICH HARMONISED TRIPARTTITE GUIDELINE, IMPURITIES IN NEW DRUG PRODUCTS Q3B(R2)(page 7)(URL: http://www.pmda.go.jp/ich/q/q3br2—06—7—3e.pdf)    Patent Document 1: International Publication No. WO03/090789 pamphlet    Patent Document 2: International Publication No. WO04/043497 pamphlet    Patent Document 3: Japanese Patent Laid-open (Kokai) No. H10-147542    Patent Document 4: International Publication No. WO04/056725 pamphlet